RU58841, a new nonsteroidal antiandrogen from Roussel Uclaf, Romainville, France, has been tested for inhibiting the androgen receptor (AR) in human hair follicles (HF). AR has been localized in HF and found to play a major role in androgenetic alopecia, as well as hirsutism. RU58841 displayed a promising activity profile when tested with AR purified from HF, giving a calculated K i 0.4 nM, inhibiting approximately 70% DHT/R1881 binding, approximately 20% better than cyproterone acetate. In short term studies we have developed cell free systems using nuclei from human scalp versusgenital skin to assess binding of AR-58841-inhibitor complexes to nuclear chromatin acceptor sites, while measuring stimulation and inhibition of RNA polymerase II, respectively. AR-58841 complexes bind very specifically to nuclear chromatin acceptor sites in both scalp and genital tissue, with > 60% reduction in RNA polymerase II in genital tissue, in comparison to control levels of androgen alone incubated. Longer term culture (up to 10 days) of whole HF frombeard of 6 male facial specimens versus scalp revealed significant differences (p<0.005) in HF growth rates, protein and DNA synthesis, ATP content, RNA polymerase II activity and thioredoxin reductase activity, whereas no changes in keratin synthesis patterns were found when adding 1 uM RU58841 with and without added DHT, respectively. Overall, RU58841 seems to be a very effective agent in binding to the AR, forming an AR-58841 complex which binds effectively to nuclear acceptor sites in scalp, genital and beard skin, and importantly effects RNA polymerase II activity. From kinetic studies we find this compound to be a mixed inhibitor, with binding to the ligand site as well as displaying allosteric binding characteristics to the regulatory domain of AR, which may be a new and novel approach for antiandrogen treatment of skin disorders, such as androgenetic alopecia and hirsutism.
